■Lurbinectedin是致癌转录的选择性抑制剂美国食品和药物管理局(FDA)批准用于复发性小细胞肺癌(SCLC)患者的单一疗法,每3周3.2mg/m2(q3wk)。ATLANTIS是SCLC的3期研究,使用lurbinectedin2.0mg/m2加多柔比星40mg/m2q3wk与医生的选择,以总生存期(OS)为主要终点,以客观缓解率(ORR)为次要终点。这项工作旨在剖析lurbinectedin和多柔比星对SCLC抗肿瘤作用的贡献,并预测3.2mg/m2的单一药物lurbinectedin在ATLANTIS中的疗效,以与对照臂进行头对头比较。
■数据集包括387例复发性SCLC患者的暴露和疗效数据(ATLANTIS,n=288;研究B-005,n=99)。使用ATLANTIS对照组的患者(n=289)进行比较。使用浓度-时间曲线下的未结合血浆lurbinectedin面积(AUCu)和浓度-时间曲线下的总血浆阿霉素面积(AUCDOX)作为暴露指标。进行单变量和多变量分析以确定OS和ORR的最佳预测因子和预测模型。OS基线危害最好通过对数Logistic分布来描述,无化疗间隔(CTFI),乳酸脱氢酶,白蛋白,脑转移瘤,中性粒细胞/淋巴细胞比率,AUCu,AUCu和AUCDOX之间的相互作用作为预测因子。AUCu对ORR的影响最适合乙状最大反应(Emax)逻辑模型,其中Emax依赖于CTFI。
■与预测的3.2mg/m2lurbinectedin的头对头比较在ATLANTIS中产生了积极的结果,OS为0.54(0.41,0.72)的危险比(95%预测间隔[95%PI]),ORR为0.35(0.25,0.5)的比值比(95%PI)。
■这些结果支持lurbinectedin单药治疗复发性小细胞肺癌优于其他批准的治疗。
UNASSIGNED: Lurbinectedin is a selective inhibitor of oncogenic transcription U.S. Food and Drug Administration (FDA)-approved for patients with relapsed small cell lung cancer (SCLC) as monotherapy at 3.2 mg/m2 every 3 weeks (q3wk).
ATLANTIS was a phase 3 study in SCLC with lurbinectedin 2.0 mg/m2 plus doxorubicin 40 mg/m2 q3wk vs physician\'s choice, with overall survival (OS) as the primary endpoint and objective response rate (ORR) as the secondary endpoint. This work aimed to dissect the contribution of lurbinectedin and doxorubicin to antitumor effects in SCLC, and to predict the efficacy of single-agent lurbinectedin at 3.2 mg/m2 in
ATLANTIS to allow for a head-to-head comparison with the control arm.
UNASSIGNED: The dataset included exposure and efficacy data from 387 patients with relapsed SCLC (
ATLANTIS, n=288; study B-005, n=99). Patients in the
ATLANTIS control arm (n=289) were used for comparison. Unbound plasma lurbinectedin area under the concentration-time curve (AUCu) and total plasma doxorubicin area under the concentration-time curve (AUCDOX) were used as exposure metrics. Univariate and multivariate analyses were conducted to determine the best predictors and predictive model for OS and ORR. OS baseline hazard was best described by a log-logistic distribution, with chemotherapy-free interval (CTFI), lactate dehydrogenase, albumin, brain metastases, neutrophils/lymphocytes ratio, AUCu, and the interaction between AUCu and AUCDOX as predictors. Effect of AUCu on ORR best fitted to a sigmoid-maximal response (Emax) logistic model, where Emax was dependent on CTFI.
UNASSIGNED: Head-to-head comparisons with predicted 3.2 mg/m2 lurbinectedin resulted in a positive outcome in
ATLANTIS, with hazard ratio (95% prediction intervals [95% PI]) for OS of 0.54 (0.41, 0.72), and odds ratio (95% PI) for ORR of 0.35 (0.25, 0.5).
UNASSIGNED: These results support the superiority of lurbinectedin monotherapy for relapsed SCLC over other approved therapies.